Antinociceptive and antidepressant-like profiles of BL-2401, a novel enkephalinase inhibitor, in mice and rats.
To clarify the properties of BL-2401 ((+/-)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5-methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressant-like activities after oral administration, along with their association with endogenous opioid systems. BL-2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED50: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg), the antinociceptive effect being antagonized by naloxone hydrochloride. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significant but modest antinociception at higher doses (200 and 400 mg/kg). In addition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepressant-like effect in the mouse forced swimming test. As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 ((+/-)-3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid), selectively inhibited enkephalinase in vitro (IC50: 5.2 nM). Oral administration of BL-2401 to mice significantly inhibited the enkephalinase activity in the striatum and also potentiated the antinociceptive effect of (D-Ala2,Met5)-enkephalin given intracisternally. These findings indicate that BL-2401 is an orally active enkephalinase inhibitor and may produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems.
Kita
A
A
Department of Pharmacology I, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
Imano
K
K
Seto
Y
Y
Yakuo
I
I
Deguchi
T
T
Nakamura
H
H
D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D016227:Benzoquinones; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000378:metabolism*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013550:Swimming
C110981:3-(2-benzyl-3-(propionylthio)propionyl)amino-5-methybenzoic acid; C110982:3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid; D000700:Analgesics; D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D001565:Benzoates; D016227:Benzoquinones; D009292:Narcotic Antagonists; D009294:Narcotics; D013438:Sulfhydryl Compounds; C110983:cassumunin A; C029322:phenylbenzoquinone; D009270:Naloxone; D004744:Enkephalin, Methionine; C013801:enkephalin-Met, Ala(2)-; D015260:Neprilysin; D003474:Curcumin